Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AOP Orphan Pharmaceuticals GmbH, Leopold-Ungar-Platz 2, 1190 Vienna, Austria
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
The recommended posology for the titration phase of ropeginterferon alfa-2b (see section 4.2) results in a prolonged time to reach the individual optimal dose compared to hydroxycarbamide. In a clinical study in polycythaemia vera, the end of the mean individual titration phase for ropeginterferon alfa-2b was reached after approximately 3.7 months, for hydroxycarbamide after approximately 2.6 months of treatment. Thus, other products (e.g., hydroxycarbamide) may be preferred in patients for whom an early reduction in elevated blood counts is necessary to prevent thrombosis and bleeding.
During the titration phase the efficacy to reduce the cardiovascular and thromboembolic risk of the underlying disease may not be fully established. Patients should be closely monitored, particularly during the titration phase; complete blood counts including determination of haematocrit level, leukocyte and platelet counts should be performed regularly also after the individual optimal dose has been established. Phlebotomy as rescue treatment to normalise blood hyperviscosity may be necessary.
Before ropeginterferon alfa-2b therapy, any pre-existing thyroid disease needs to be treated and controlled with conventional therapy (see section 4.3). Patients who develop symptoms indicative of a thyroid dysfunction during ropeginterferon alfa-2b therapy, should evaluate their thyroid stimulating hormone (TSH) levels. If TSH levels can be controlled within the normal range, the therapy can be continued.
Diabetes mellitus have been observed with other interferon alfa medicinal products (see section 4.8). Patients with this condition who cannot be effectively controlled by medicinal products should not begin ropeginterferon alfa-2b therapy. Patients who develop this condition during treatment and cannot be controlled by medicinal products should discontinue ropeginterferon alfa-2b therapy.
CNS effects, particularly depression, have been observed in some patients treated with ropeginterferon alfa-2b during the clinical development program (see section 4.8). Other CNS effects, including suicidal ideation, attempted suicide, aggression, bipolar disorder, mania and confusion have been observed with other interferon alfa medicinal products. Patients should be closely monitored for any symptoms of psychiatric disorders and therapeutic management should be considered by the treating physician if such symptoms emerge. If psychiatric symptoms worsen, it is recommended to discontinue ropeginterferon alfa-2b therapy. Ropeginterferon alfa-2b must not be administered in patients with existence of or history of severe psychiatric disorders, particularly severe depression, suicidal ideation or suicide attempt (see section 4.3).
Cardiac events including cardiomyopathy, myocardial infarction, atrial fibrillation and ischaemic coronary artery disorders have been associated with interferon alfa treatment (see section 4.8). Patients with pre-existing or a history of cardiovascular disorders should be closely monitored during ropeginterferon alfa-2b therapy. This medicinal product is contraindicated in patients with severe pre-existing cardiovascular disease or patients who had recently suffered from a stroke or myocardial infarction (see section 4.3).
Respiratory disorders such as lung infiltration, pneumonitis, pneumonia or pulmonary arterial hypertension have been observed rarely in patients treated with interferon alfa (see section 4.8). Patients who develop respiratory symptoms should be monitored closely and if necessary, ropeginterferon alfa-2b therapy should be discontinued.
Severe eye disorders such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion which may result in blindness have been observed rarely in patients treated with interferon alfa (see section 4.8). Patients should have eye examinations before and during ropeginterferon alfa-2b therapy, specifically in those patients with retinopathy associated disease such as diabetes mellitus or hypertension. Any patient reporting a decrease or loss of vision or reporting other eye symptoms should have an immediate eye examination. Discontinuation of ropeginterferon alfa-2b should be considered in patients who develop new or worsening eye disorders.
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed with other interferon alfa medicinal products. If this occurs, ropeginterferon alfa-2b therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.
Interferon alfa therapy has been associated with hepatotoxicity characteried by potentially significant increases in liver enzymes. Hepatic failure in hepatitis C virus infected patients was reported with other interferon alfa medicinal products (see section 4.8).
Increases in ALT (≥3 times the upper limit of normal), AST (≥3 times the upper limit of normal), GGT (≥3 times the upper limit of normal) and bilirubin (>2 times the upper limit of normal) levels have been observed in patients treated with ropeginterferon alfa-2b. These elevations were mostly transient and occurred during the first treatment year.
Liver disorders have been reported in patients after long-term ropeginterferon alfa-2b therapy (see section 4.8). Liver enzymes and hepatic function should be regularly controlled in patients with longterm ropeginterferon alfa-2b therapy. Treatment with ropeginterferon alfa-2b should be discontinued when, despite dose reduction, the increase in liver enzyme levels is progressive and clinically significant. In patients who develop evidence of hepatic decompensation during treatment, ropeginterferon alfa-2b should be discontinued. Ropeginterferon alfa-2b is contraindicated in patients with decompensated cirrhosis of the liver (see section 4.3).
Regardless of the starting dose or degree of renal impairment, patients should be monitored. If renal function decreases during treatment, ropeginterferon alfa-2b therapy should be discontinued. Ropeginterferon alfa-2b is contraindicated in patients with end stage renal disease (see section 4.3).
Dental and periodontal disorders, which may lead to loss of teeth, have been reported with other interferon alfa medicinal products (see section 4.8). In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with ropeginterferon alfa-2b. Patients should brush their teeth thoroughly twice daily and have regular dental examinations.
The use of ropeginterferon alfa-2b is associated with skin disorders (pruritus, alopecia, rash, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, hyperhydrosis). In case of appearance or worsening of this skin disorders, the stop of the treatment must be envisaged.
Besremi contains benzyl alcohol.
High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).
Besremi contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially ‘sodium-free’.
Enzymes of the protein catabolism are considered to be involved in the metabolism of ropeginterferon alfa-2b. The involvement of transport proteins in absorption, distribution and elimination of ropeginterferon alfa-2b is not known. Interferon alfa has shown to influence the activity of cytochrome P450 (CYP) isozymes CYP1A2 and CYP2D6.
No interaction studies have been performed with ropeginterferon alfa-2b.
Co-administration of pegylated interferon alfa-2a with telbivudine in patients with hepatitis B increased the risk of developing peripheral neuropathy. A combination therapy with telbivudine and ropeginterferon alfa-2b is contraindicated (see section 4.3).
Administration of 180 micrograms of pegylated interferon alfa-2a once weekly for 4 weeks in healthy male subjects did not show any effect on mephenytoin, dapsone, debrisoquine and tolbutamide pharmacokinetics profiles, suggesting that pegylated interferon alfa-2a has no effect on in vivo metabolic activity of cytochrome P450 (CYP) 3A4, 2C9, 2C19 and 2D6 isozymes. In the same study, a 25% increase in the AUC of theophylline (CYP1A2 substrate) was observed, demonstrating that pegylated interferon alfa-2a is an inhibitor of CYP1A2 activity.
Co-administration of pegylated interferon alfa-2b showed no significant interaction with tolbutamide (CYP2C9 substrate), midazolam (CYP3A4 substrate), dapsone (N-acetyltransferase substrate) and modestly increased the exposure of caffeine (CYP1A2 substrate) and desipramine (CYP2D6 substrate).
Therefore, care should be taken when ropeginterferon alfa-2b is co-administered with CYP1A2 substrates notably those having a narrow therapeutic margin such as theophylline or methadone. Likewise, caution is recommended with CYP2D6 substrates (e.g., vortioxetine, risperidone) combined with ropeginterferon alfa-2b. Ropeginterferon alfa-2b may inhibit the activity of CYP1A2 and CYP2D6 and thus may increase the blood concentrations of these medicinal products.
No dose adaptions for ropeginterferon alfa-2b should be necessary when concomitantly administered with medicinal products metabolised via CYP2C9/19, CYP3A4 or by N-acetyltransferase.
Caution must be exercised when administering ropeginterferon alfa-2b in combination with other potentially myelosuppressive/chemotherapeutic agents.
Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with ropeginterferon alfa-2b.
Women of childbearing potential must use effective contraception during the treatment with ropeginterferon alfa-2b, unless otherwise discussed with the physician.
There are no or limited amount of data from the use of interferon alfa in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3).
As ropeginterferon alfa-2b may have the same effect, Besremi is not recommended during pregnancy and in women of childbearing potential not using contraception.
It is not known whether ropeginterferon alfa-2b is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Besremi therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.
There are no data on the effect of ropeginterferon alfa-2b therapy on the fertility of females or males.
Besremi has minor influence on the ability to drive and use machines. Patients who experience dizziness, somnolence or hallucination (see section 4.8) during Besremi therapy should avoid driving or using machines.
The most common adverse reactions are leukopenia (20.2%), thrombocytopenia (18.5%), arthralgia (13.5%), fatigue (12.4%), increased gamma-glutamyltransferase (11.2%), influenza-like illness (11.2%), myalgia (10.7%), anaemia (9.6%), increased alanine aminotransferase (8.4%), neutropenia (7.9%), pyrexia (7.9%), increased aspartate aminotransferase (7.3%), pruritus (6.8%), pain in extremity (6.7%), alopecia (6.7%), headache (6.2%), diarrhoea (5.7%), injection site reaction (5.6%), chills (5.1%), and dizziness (5.1%).
Serious adverse reactions are depression (1.1%), atrial fibrillation (1.1%) and acute stress disorder (0.6%).
Following treatment-related adverse reactions were reported with ropeginterferon alfa-2b in clinical studies in 178 polycythaemia vera adult patients. Adverse reactions are listed by system organ class and frequency (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) or not known (cannot be estimated from available data).
| System organ class | Frequency | Adverse reaction |
|---|---|---|
| Infections and infestations | common | respiratory tract infection, influenza, rhinitis, fungal skin infection |
| uncommon | oral herpes, herpes zoster, oral candidiasis, sinusitis, oesophageal candidiasis, vulvovaginal mycotic infection, hordeolum, onychomycosis | |
| Blood and lymphatic system disorders | very common | leukopenia, thrombocytopenia |
| common | pancytopenia, neutropenia, anaemia | |
| Immune system disorders | uncommon | sarcoidosis |
| very rare | idiopathic or thrombotic thrombocytopenic purpura# | |
| not known | Vogt-Koyanagi-Harada disease#, acute hypersensitivity reactions#** | |
| Endocrine disorders | common | hypothyroidism, hyperthyroidism, thyroiditis |
| uncommon | Basedow’s disease, diabetes mellitus# | |
| Metabolism and nutrition disorders | common | hypertriglyceridaemia, decreased appetite |
| Psychiatric disorders | common | depression, aggression#, insomnia, anxiety, mood altered, mood swings, mood disorders |
| uncommon | suicide attempt#, suicidal ideation#, confusional state#, acute stress disorder, hallucination, emotional distress, nervousness nightmare, irritability | |
| rare | bipolar disorder#, mania# | |
| Nervous system disorders | common | headache, dizziness, hypoesthesia, somnolence, paraesthesia |
| uncommon | polyneuropathy, peripheral motor neuropathy, radiculopathy, migraine, mental impairment, tremor, aura | |
| Eye disorders | common | dry eye |
| uncommon | retinal haemorrhage#, retinal exudates#, visual impairment, visual acuity reduced, vision blurred, ocular discomfort, eczema eyelids | |
| rare | retinopathy#, optic neuropathy#, retinal artery occlusion#, retinal vein occlusion# | |
| very rare | blindness# | |
| not known | retinal detachment# | |
| Ear and labyrinth disorders | uncommon | deafness, tinnitus, vertigo |
| Cardiac disorders | common | atrial fibrillation |
| uncommon | myocardial infarction#, atrioventricular block, intracardiac thrombus, aortic valve incompetence, cardiovascular disorder | |
| rare | cardiomyopathy#, angina pectoris# | |
| very rare | myocardial ischemia# | |
| Vascular disorders | common | microangiopathy |
| uncommon | Raynaud’s phenomenon, hypertension, haematoma, flushing | |
| Respiratory, thoracic and mediastinal disorders | common | dyspnoea |
| uncommon | pneumonitis, cough, epistaxis, throat irritation | |
| very rare | lung infiltration# | |
| not known | pulmonary fibrosis#, pneumonia#, pulmonary arterial hypertension#* | |
| Gastrointestinal disorders | common | diarrhoea, nausea, abdominal pain, constipation, abdominal distension, dry mouth |
| uncommon | gastritis, abdominal wall disorder, flatulence, frequent bowel movements, odynophagia, gingival bleeding | |
| not known | tooth disorder#, periodontal disease# | |
| Hepatobiliary disorders | very common | gamma-glutamyltransferase increased |
| common | liver disorder, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased | |
| uncommon | hepatotoxicity, hepatitis toxic, hepatomegaly, porphyria non-acute | |
| rare | hepatic failure# | |
| Skin and subcutaneous tissue disorders | common | pruritus, alopecia, rash, erythema, psoriasis, xeroderma, dermatitis acneiform, hyperkeratosis, hyperhidrosis, dry skin |
| uncommon | photosensitivity reaction, skin exfoliation, nail dystrophy | |
| not known | skin depigmentation# | |
| Musculoskeletal and connective tissue disorders | very common | arthralgia, myalgia |
| common | Sjogren’s syndrome, arthritis, pain in extremity, musculoskeletal pain, bone pain, muscle spasms | |
| uncommon | muscular weakness, neck pain, groin pain | |
| Renal and urinary disorders | uncommon | cystitis haemorrhagic, dysuria, micturition urgency, urinary retention |
| Reproductive system and breast disorders | uncommon | erectile dysfunction, haematospermia |
| General disorders and administration site conditions | very common | influenza-like illness, fatigue |
| common | pyrexia, injection site reaction, asthenia, chills, general physical health deterioration, injection site erythema | |
| uncommon | injection site pain, injection site pruritus, sensitivity to weather change | |
| not known | tongue hyperpigmentation# | |
| Investigations | common | antithyroid antibody positive, blood thyroid stimulating hormone increased, body temperature increased, antinuclear antibody positive, blood lactate dehydrogenase increased, weight decreased |
| uncommon | platelet count increased, blood uric acid increased, Coombs test positive |
# Reported as adverse reactions during treatment with other interferon alfa medicinal products.
* Class label for interferon medicinal products, see below pulmonary arterial hypertension.
** e.g., urticaria, angioedema, bronchoconstriction, or anaphylaxis.
The most common adverse reactions (including number of patients, incidence rate, severity grade, necessity for dose adaptation and outcome) reported during the ropeginterferon alfa-2b clinical development program are summarised in Table 1.
Table 1. Most common adverse reactions during ropeginterferon alfa-2b treatment:
| ADR >10% PT | N (%) N=178 | IR | CTCAE intensity grade ≥3 N (%) | Dose reduced N (%) | Medicinal Product interrupted N (%) | Medicinal Product discontinued N (%) | Recovered N (%) |
|---|---|---|---|---|---|---|---|
| Leukopenia | 36 (20.2%) | 21.2 | 3 (8.3) | 5 (13.9) | 4 (11.1) | n.r. | 8 (22.2) |
| Thrombocytopenia | 33 (18.5%) | 11.2 | 4 (12.1) | 3 (9.1) | 2 (6.1) | n.r. | 6 (18.2) |
| Arthralgia | 24 (13.5%) | 5.2 | 1 (4.2) | 4 (16.7) | 3 (12.5) | 1 (4.2) | 15 (62.5) |
| Fatigue | 22 (12.4%) | 6.6 | n.r. | 3 (13.6) | 1 (4.5) | 1 (4.5) | 11 (50.0) |
| Gamma-glutamyl- transferase increased | 20 (11.2%) | 7.9 | 7 (35.0) | 3 (15.0) | n.r. | n.r. | 4 (20.0) |
| Influenza like illness | 20 (11.2%) | 4.9 | n.r. | 4 (20.0) | 2 (10.0) | n.r. | 10 (50.0) |
| Myalgia | 19 (10.7%) | 3.5 | n.r. | 2 (10.5) | 1 (5.3) | n.r. | 9 (47.4) |
No CTCAE grade 5 (death) adverse reactions reported for these preferred terms; 1 AE grade 4 (life-threating or disabling) reported for Gamma-glutamyltransferase increased.
Abbreviations: CTCAE, common terminology criteria for adverse events; n.r., not reported; ADR, adverse drug reaction; PT, preferred term; IR, incidence rate of mean adverse events per 100 patients per year; N, number of patients.
N (%) number and percentage of patients with given AE
Gastrointestinal disorders have been reported with other interferon alfa medicinal products and have been reported in 15.7% of patients with ropeginterferon alfa-2b treatment. The most common gastrointestinal disorders reported in these studies were diarrhoea (5.1%; incidence rate: 2.8 [events/100 patients per year]) and nausea (4.5%; incidence rate: 1.2 events/100 patients per year]).
In the clinical development program of ropeginterferon alfa-2b, two cases of serious depression (1.1%; incidence rate: 0.4 events/100 patients per year) occurred. The patients recovered completely after permanent medicinal product discontinuation. One patient who experienced serious acute stress disorder (0.6%; incidence rate: 0.2 events/100 patients per year) with moderate intensity recovered completely after the dose of ropeginterferon alfa-2b was reduced. CNS effects including suicide attempt, suicidal ideation, aggression, bipolar disorder, mania and confusion have been reported with interferon alfa (see section 4.4).
During ropeginterferon alfa-2b therapy, three cases of atrial fibrillation (1.1%; incidence rate: 0.3 events/100 patients per year) with intensity grade 1 to 3 occurred in two patients. Ropeginterferon alfa-2b treatment was continued, and the patients received appropriate medicinal products to treat these events. Patients recovered from the two events; one event was ongoing at the time of assessment.
Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa, notably in patients with risk factors for PAH (such as portal hypertension, HIV infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.
Serious eye disorders have been reported with interferon alfa such as retinopathy, retinal haemorrhage, retinal exudates, retinal detachment and retinal artery or vein occlusion (see section 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
Not applicable.
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